Project Summary The overall objective of the proposed research is to determine the mechanism of action of an antidepressant of known efficacy and tie this mechanism of action to a specific biomarker, ultimately supporting precision medicine in the treatment of major depression (MD). More specifically, the proposed research is designed to determine whether bupropion (vs escitalopram) increases functional connectivity (FC) within reward-related neurocircuits and decreases motivational deficits in depressed patients with increased inflammation and anhedonia. Work by our group and others has demonstrated that administration of inflammatory stimuli to humans is associated with significant decreases in neural activity in the ventral striatum in association with symptoms of anhedonia. In studies in laboratory animals and humans, these effects of inflammation appear to be secondary to decreased dopamine (DA) neurotransmission. Data also indicate that MD patients with higher inflammation as indexed by C-reactive protein (CRP) exhibit lower FC between the DA-rich ventral striatum and ventromedial prefrontal cortex in association with motivational deficits and anhedonia that can be reversed by a DAergic drug (L-DOPA). Further relevant to the proposed research, in a recent clinical trial, depressed patients with increased inflammation (CRP?1mg/L) showed a poor response to the selective serotonin reuptake inhibitor (SSRI) escitalopram alone, while treatment response was markedly increased in escitalopram-treated patients with the addition of bupropion. Bupropion is a DA reuptake inhibitor that exhibits ~25% occupancy of the DA transporter at therapeutic doses and increases DA neurotransmission in animal models. Taken together, these data suggest that inflammation affects DAergic pathways to disrupt reward- related circuits in depressed patients, leading to motivational deficits. Moreover, in the context of inflammation, drugs that target DA may be more efficacious than SSRIs. Thus, the current study proposes to use a mechanistic clinical trial design with drugs of known efficacy to take the first step toward establishing whether antidepressants that target DA (e.g. bupropion) might be a better choice for depressed patients with increased inflammation and anhedonia than an SSRI. Accordingly, 50 depressed patients with a CRP>2mg/L and increased anhedonia will be randomized to 6 weeks of bupropion or escitalopram. All depressed patients will undergo resting state FC at baseline and 6 weeks along with objective and clinical assessments of RDoC positive (motivational) valence constructs at baseline and 2, 4 and 6 weeks. We hypothesize that patients who receive bupropion versus escitalopram will exhibit increased FC between ventral striatum and ventromedial prefrontal cortex in association with decreased motivational deficits and anhedonia. This pilot study will provide foundational data for design of larger mechanistic clinical trials that will establish the mechanism of action of conventional antidepressants and determine whether biomarkers of inflammation can be used to facilitate antidepressant choice, increase antidepressant efficacy and ultimately personalize antidepressant treatment.